U.S. Pat. Nos. 3,979,399, 3,840,546, and 3,966,746 (E.R. Squibb & Sons) disclose 4-amino pyrazolo[3,4-b]pyridine-5-carboxamide compounds of the following formula and salts thereof:

In U.S. Pat. No. 3,979,399, the 4-amino group NR3R4 can be an acyclic amino group wherein R3 and R4 may each be hydrogen, lower alkyl, lower alkenyl, lower alkanoyl, phenyl, substituted phenyl, phenyl-lower alkyl, di-lower alkyl amino-lower alkyl, benzoyl, substituted benzoyl, phenyl-lower alkanoyl, substituted phenyl-lower alkanoyl, lower alkanesulfonyl, benzenesulfonyl, or substituted benzenesulfonyl. NR3R4 can alternatively be a 3, 4, 5 or 6 membered heterocyclic group optionally including an additional heteroatom such as N, O or S. In preferred embodiments, R3 is lower alkyl, most preferably butyl and/or R4 is hydrogen; or R3 and R4 together with the nitrogen to which they are attached form a 5 or 6 membered heterocyclic such as pyrrolidino, piperidino or piperazino. In the 5-carboxamide group C(O)NR5R6, NR5R6 can be an acyclic amino group wherein R5 and R6 may each be hydrogen, lower alkyl, alkoxy lower alkyl, dialkoxy lower alkyl, or di-loweralkylamino-lower alkyl; or NR5R6 can be heterocyclic containing 5, 6 or 7 members in which an additional heteroatom such as N, O or S may optionally be included. In U.S. Pat. No. 3,979,399, the 1-substituent (on the pyrazolo-1-nitrogen) R1 is hydrogen, lower alkyl, phenyl, phenyl-lower alkyl, or cycloalkyl; preferably hydrogen or lower alkyl; most preferably hydrogen or ethyl. The 3-substituent R2 is hydrogen, lower alkyl or phenyl; preferably hydrogen or lower alkyl; most preferably hydrogen or methyl. The 6-substituent R7 is H, lower alkyl or phenyl, most preferably H or methyl. In U.S. Pat. No. 3,979,399, lower alkyl and lower alkenyl are defined as including straight or branched chain hydrocarbon groups containing 1 to 8 carbon atoms; examples of the type of group contemplated in U.S. Pat. No. 3,979,399 being methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc. and corresponding compounds having one double bond.
In U.S. Pat. No. 3,979,399, Example 1 is 4-butylamino-1-ethyl-pyrazolo[3,4-b]pyridine-5-(N-butyl)carboxamide hydrochloride, and Example 19 is the compound wherein R1 is (CH3)2CH—, R2 is H, R3 is —CH(CH3)C2H5, R4 is H, R5 is Ph, and R6 and R7 are H.
The compounds of U.S. Pat. No. 3,979,399 are disclosed therein as being central nervous system depressants useful as ataractic, analgesic and hypotensive agents, e.g. for oral or parenteral administration.
U.S. Pat. Nos. 3,925,388, 3,856,799, 3,833,594 and 3,755,340 (E.R. Squibb & Sons) disclose 4-amino derivatives of pyrazolo[3,4-b]pyridine-5-carboxylic acids and esters. The 4-amino group NR3R4 can be an acyclic amino group wherein R3 and R4 may each be hydrogen, lower alkyl (e.g. butyl), phenyl, etc.; NR3R4 can alternatively be a 5-6-membered heterocyclic group in which an additional nitrogen is present such as pyrrolidino, piperidino, pyrazolyl, pyrimidinyl, pyridazinyl or piperazinyl. The compounds are mentioned as being central nervous system depressants useful as ataractic agents or tranquilizers, as having antiinflammatory and analgesic properties. The compounds are mentioned as increasing the intracellular concentration of adenosine-3′,5′-cyclic monophosphate and for alleviating the symptoms of asthma.
H. Hoehn et al., J. Heterocycl. Chem., 1972, 9(2), 235-253 discloses a series of 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives with 4-hydroxy, 4-chloro, 4-alkoxy, 4-hydrazino, and 4-amino substituents.
CA 1003419, CH 553 799 and T. Denzel, Archiv der Pharmazie, 1974, 307(3), 177-186 disclose 4,5-disubstituted 1H-pyrazolo[3,4-b]pyridines unsubstituted at the 1-position.
Japanese laid-open patent application JP-2002-20386-A (Ono Yakuhin Kogyo K K) published on 23 Jan. 2002 discloses pyrazolopyridine compounds of the following formula:
wherein R1 denotes 1) a group —OR6, 2) a group —SR7, 3) a C2-8 alkynyl group, 4) a nitro group, 5) a cyano group, 6) a C1-8 alkyl group substituted by a hydroxy group or a C1-8 alkoxy group, 7) a phenyl group, 8) a group —C(O)R8, 9) a group —SO2NR9R10, 10) a group —NR11SO2R12, 11) a group —NR13C(O)R14 or 12) a group —CH═NR15. R6 and R7 denote i) a hydrogen atom, ii) a C1-8 alkyl group, iii) a C1-8 alkyl group substituted by a C1-8 alkoxy group, iv) a trihalomethyl group, v) a C3-7 cycloalkyl group, vi) a C1-8 alkyl group substituted by a phenyl group or vii) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms. R2 denotes 1) a hydrogen atom or 2) a C1-8 alkoxy group. R3 denotes 1) a hydrogen atom or 2) a C1-8 alkyl group. R4 denotes 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a C1-8 alkyl group substituted by a C3-7 cycloalkyl group, 5) a phenyl group which may be substituted by 1-3 halogen atoms or 6) a 3-15 membered mono-, di- or tricyclic hetero ring containing 1-4 nitrogen atoms, 1-3 oxygen atoms and/or 1-3 sulphur atoms. R5 denotes 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C3-7 cycloalkyl group, 4) a C1-8 alkyl group substituted by a C3-7 cycloalkyl group or 5) a phenyl group which may be substituted by 1-3 substituents. In group R3, a hydrogen atom is preferred. In group R4, methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl are preferred. The compounds of JP-2002-20386-A are stated as having PDE4 inhibitory activity and as being useful in the prevention and/or treatment of inflammatory diseases and many other diseases.
1,3-Dimethyl-4-(arylamino)-pyrazolo[3,4-b]pyridines with a 5-C(O)NH2 substituent similar or identical to those in JP-2002-20386-A were disclosed as orally active PDE4 inhibitors by authors from Ono Pharmaceutical Co. in: H. Ochiai et al., Bioorg. Med. Chem. Lett., 5 Jan. 2004 issue, vol. 14(1), pp. 29-32 (available on or before 4 Dec. 2003 from the Web version of the journal: “articles in press”).
EP 0 076 035 A1 (ICI Americas) discloses pyrazolo[3,4-b]pyridine derivatives as central nervous system depressants useful as tranquilizers or ataractic agents for the relief of anxiety and tension states.
The compound cartazolate, ethyl 4-(n-butylamino)-1-ethyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxylate, is known. J. W. Daly et al., Med. Chem. Res., 1994, 4, 293-306 and D. Shi et al., Drug Development Research, 1997, 42, 41-56 disclose a series of 4-(amino)substituted 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid derivatives, including ethyl 4-cyclopentylamino-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate, and their affinities and antagonist activities at A1- and A2A-adenosine receptors, and the latter paper discloses their affinities at various binding sites of the GABAA-receptor channel. S. Schenone et al., Bioorg. Med. Chem. Lett., 2001, 11, 2529-2531, and F. Bondavalli et al., J. Med. Chem., 2002, vol. 45 (Issue 22, 24 Oct. 2002, allegedly published on Web Sep. 24, 2002), pp. 4875-4887 disclose a series of 4-amino-1-(2-chloro-2-phenylethyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl esters as A1-adenosine receptor ligands.
WO 02/060900 A2 appears to disclose, as MCP-1 antagonists for treatment of allergic, inflammatory or autoimmune disorders or diseases, a series of bicyclic heterocyclic compounds with a —C(O)—NR4—C(O)—NR5R6 substituent, including isoxazolo[5,4-b]pyridines and 1H-pyrazolo[3,4-b]pyridines (named as pyrazolo[5,4-b]pyridines) with the —C(O)—NR4—C(O)—NR5R6 group as the 5-substituent and optionally substituted at the 1-, 3-, 4-, and/or 6-positions. Bicyclic heterocyclic compounds with a —C(O)NH2 substituent instead of the —C(O)—NR4—C(O)—NR5R6 substituent are alleged to be disclosed in WO 02/060900 as intermediates in the synthesis of the —C(O)—NR4—C(O)—NR5R6 substituted compounds.
WO 00/15222 (Bristol-Myers Squibb) discloses inter alia pyrazolo[3,4-b]pyridines having either a C(O)—X1 group at the 5-position and a group E1 at the 4-position of the ring system or C(O)—X2 group at the 5-position and a group E2 at the 4-position of the ring system. X1 and X2 are —OR or —NRR. E1 is —NH-A1-cycloalkyl, —NH-A1-substituted cycloalkyl, —NH-A1-heterocyclo, —NH-A1-heteroaryl, et al. E2 is —NH-A1-alkoxy, —NH-A1-CO2alkyl, —NH-A1-N(R15)(R16), —NH-A1-aryl or —NH-A1-substituted aryl. A1 is an alkylene or substituted alkylene bridge of 1 to 10 carbons. The compounds are disclosed as being useful as inhibitors of cGMP phosphodiesterase, especially PDE type V, and in the treatment of various cGMP-associated conditions such as erectile dysfunction. 4-alkylamino-pyrazolo[3,4-b]pyridines and/or PDE4 inhibitory activity do not appear to be disclosed in WO 00/15222.
Copending patent application PCT/EP03/11814, filed on 12 Sep. 2003 in the name of Glaxo Group Limited and incorporated herein by reference, discloses pyrazolo[3,4-b]pyridine compounds or salts thereof with a 4-NHR3 group and a 5-C(O)—X group, according to this formula (I):
wherein:
R1 is C1-4alkyl, C1-3fluoroalkyl, —CH2CH2OH or —CH2CH2CO2C1-2alkyl;
R2 is a hydrogen atom (H), methyl or C1 fluoroalkyl;
R3 is optionally substituted C3-8cycloalkyl or optionally substituted mono-unsaturated-C5-7cycloalkenyl or an optionally substituted heterocyclic group of sub-formula (aa), (bb) or (cc);

in which n1 and n2 independently are 1 or 2; and in which Y is O, S, SO2, or NR10;
or R3 is a bicyclic group (dd) or (ee):

and wherein X is NR4R5 or OR5a.
In PCT/EP03/11814, R4 is a hydrogen atom (H); C1-6alkyl; C1-3fluoroalkyl; or C2-6alkyl substituted by one substituent R11.
In PCT/EP03/11814, R5 can be: a hydrogen atom (H); C1-8alkyl; C1-8 fluoroalkyl; C3-8cycloalkyl optionally substituted by a C1-2alkyl group; —(CH2)n4—C3-8cycloalkyl optionally substituted, in the —(CH2)n4— moiety or in the C3-8cycloalkyl moiety, by a C1-2alkyl group, wherein n4 is 1, 2 or 3; C2-6alkyl substituted by one or two independent substituents R11; —(CH2)n11—C(O)R16; —(CH2)n12—C(O)NR12R13; —CHR19—C(O)NR12R13; —(CH2)n12—C(O)OR16; —(CH2)n12—C(O)OH; —CHR19—C(O)OR16; —CHR19—C(O)OH; —(CH2)n12—SO2—NR12R13; —(CH2)n12—SO2R16; or —(CH2)n12—CN; —(CH2)n13-Het; or optionally substituted phenyl. Alternatively, in PCT/EP03/11814, R5 can have the sub-formula (x), (y), (y1) or (z):
wherein in sub-formula (x), n=0, 1 or 2; in sub-formula (y) and (y1), m=1 or 2; and in sub-formula (z), r=0, 1 or 2; and wherein in sub-formula (x) and (y) and (y1), none, one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N+—O−) provided that no more than one of A, B, D, E and F is nitrogen-oxide, and the remaining of A, B, D, E and F are independently CH or CR6; and provided that when n is 0 in sub-formula (x) then one or two of A, B, D, E and F are independently nitrogen or nitrogen-oxide (N+—O−) and no more than one of A, B, D, E and F is nitrogen-oxide;
In PCT/EP03/11814, each R6, independently of any other R6 present, is: a halogen atom; C1-6alkyl; C1-4fluoroalkyl; C1-4alkoxy; C1-2fluoroalkoxy; C3-6cycloalkyloxy; —C(O)R16a; —C(O)OR30; —S(O)2—R16a; R16a—S(O)2—NR15a—; R7R8N—S(O)2—; C1-2alkyl-C(O)—R15aN—S(O)2—; C1-4alkyl-S(O)—; Ph-S(O)—; R7R8N—CO—; —NR15—C(O)R16; R7R8N; OH; C1-4alkoxymethyl; C1-4alkoxyethyl; C1-2alkyl-S(O)2—CH2—; R7R8N—S(O)2—CH2—; C1-2alkyl-S(O)2—NR15a—CH2—; —CH2—OH; —CH2CH2—OH; —CH2—NR7R8; —CH2—CH2—NR7R8; —CH2—C(O)OR30; —CH2—C(O)—NR7R8; —CH2—NR15a—C(O)—C1-3alkyl; —(CH2)n14-Het1 where n14 is 0 or 1; cyano (CN); Ar5b; or phenyl, pyridinyl or pyrimidinyl wherein the phenyl, pyridinyl or pyrimidinyl independently are optionally substituted by one or two of fluoro, chloro, C1-2alkyl, C1 fluoroalkyl, C1-2alkoxy or C1 fluoroalkoxy;                or two adjacent R6 taken together can be —O—(CMe2)—O— or —O—(CH2)n14—O— where n14 is 1 or 2.        
In PCT/EP03/11814, in sub-formula (z), G is O or S or NR9 wherein R9 is a hydrogen atom (H), C1-4alkyl or C1-4fluoroalkyl; none, one, two or three of J, L, M and Q are nitrogen; and the remaining of J, L, M and Q are independently CH or CR6 where R6, independently of any other R6 present, is as defined therein.
The pyrazolo[3,4-b]pyridine compounds of formula (I) and salts thereof disclosed in PCT/EP03/11814 are disclosed as being inhibitors of phosphodiesterase type IV (PDE4), and as being useful for the treatment and/or prophylaxis of an inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, or allergic rhinitis.